The overall goal of this proposal is to assess the importance of DNA recombination and DNA repair processes in brain plasticity and complex behaviors. Long-term memory is known to require the production of new proteins in the brain via the regulation of gene transcription and translation mechanisms. Additionally, several reports have postulated the idea that regulation of gene expression and function by DNA recombination mechanisms may also be involved in learning and memory processes. DNA repair mechanisms are tightly associated to recombination processes, such as those utilized in the immune system, which involve DNA cutting, repair, and rejoining (or ligation) mechanisms. Our preliminary studies with a drug that blocks the repair and rejoining of DNA, known as ara-CTP, strongly implicate these processes in the formation of long-term memory in the brain. The experiments proposed here will test specific hypotheses regarding the functional significance of DNA recombination and repair mechanisms in learning and memory processes of the brain. In Specific Aim 1 we hypothesize that ara-CTP impairs memory formation in hippocampal and amygdala dependent behavioral tasks. Just prior to training, ara-CTP, its precursor agent ara-C, or control solution, are injected directly into the brain of rats in order to reach important learning and memory structures. Learning and long-term memory is assessed in rats. Biochemical processes subserving the effects of ara-CTP will also be studied. In Specific Aim 2 we explore the hypothesis that blockade of memory by ara-C is due to an impairment in the regulation of genes important for learning and memory that might be directly or indirectly regulated by DNA recombination in the brain. For these studies we combine the behavioral experiments with gene expression profiling with microarrays. Results from this work will provide fundamental knowledge concerning how the brain stores information, which may help understand the pathophysiology of neurodegenerative and psychiatric diseases, such as Alzheimer's disease and post-traumatic stress syndrome.